title: Rho-kinase inhibition ameliorates peritoneal fibrosis and angiogenesis in a rat model of peritoneal sclerosis.
abstract: BACKGROUND
  Peritoneal fibrosis (PF) and angiogenesis are typical morphological changes, leading to loss of peritoneal functions in patients undergoing peritoneal dialysis. The small G protein, Rho, and its downstream effector Rho-kinase have been shown to be involved in the tissue fibrosis process. This study was undertaken to investigate the role of Rho-kinase in the pathogenesis of these alterations.
  
  
  METHODS
  PF was induced by intraperitoneal administration of chlorhexidine (CHX) in male rats (CHX group). These rats were treated with a Rho-kinase inhibitor, fasudil (Fas group). Human pleural mesothelial cells, MeT-5A cells, were stimulated by glucose with or without another Rho-kinase inhibitor, Y-27632.
  
  
  RESULTS
  Peritoneal damage including peritoneal thickening, fibrous changes, macrophage migration and angiogenesis were evident in the CHX group and were ameliorated in the Fas group. The expression of markers of tissue fibrosis, such as transforming growth factor (TGF)-β, fibronectin and α-smooth muscle cell actin, were increased in the CHX group and were downregulated by fasudil. Similar results were also seen with an inducer of angiogenesis, vascular endothelial growth factor (VEGF). Rho-kinase was activated in the peritoneum of the CHX group, which was inhibited by fasudil. In MeT-5A cells, high glucose increased TGF-β expression and VEGF secretion, which were blocked by Y-27632.
  
  
  CONCLUSIONS
  The activation of Rho-kinase is involved in peritoneal damage at multiple stages including tissue fibrosis and angiogenesis. The inhibition of Rho-kinase constitutes a novel strategy for the treatment of PF.
authors.affiliation: Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Washida
authors.forename: Shu
authors.initials: S
authors.lastname: Wakino
authors.forename: Yukio
authors.initials: Y
authors.lastname: Tonozuka
authors.forename: Koichiro
authors.initials: K
authors.lastname: Homma
authors.forename: Hirobumi
authors.initials: H
authors.lastname: Tokuyama
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Hara
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Hasegawa
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Minakuchi
authors.forename: Keiko
authors.initials: K
authors.lastname: Fujimura
authors.forename: Kohji
authors.initials: K
authors.lastname: Hosoya
authors.forename: Koichi
authors.initials: K
authors.lastname: Hayashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Itoh
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000577:Amides / Q000627:therapeutic use*; D000818:Animals; D000891:Anti-Infective Agents, Local / Q000494:pharmacology; D002478:Cells, Cultured; D002710:Chlorhexidine / Q000494:pharmacology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D056627:Peritoneal Fibrosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D035422:Pleural Cavity / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D000577:Amides; D000891:Anti-Infective Agents, Local; D004791:Enzyme Inhibitors; D011725:Pyridines; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; C108830:Y 27632; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; C049347:fasudil; D002710:Chlorhexidine